Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene codes for a protein highly related to the ERM proteins moesin, ezrin and radixin and was thus termed merlin. The ERM proteins are thought to function as cell membrane-cytoskeleton linkers. Merlin is regulated, at least in part, by Rac/cdc42-dependent phosphorylation. Recent data implicates merlin as a possible negative regulator of the Rac/cdc42 signaling pathway. The proposed project focuses on the study of the tumor suppressive properties of merlin and the signaling pathways connecting extracellular signals to cytoskeletal organization and/or the proliferative state of the cell, via merlin. The work involves two combined approaches: 1) Understanding how merlin might interact with and regulate, the Rac/cdc42 signaling pathway. 2) Structure/function studies of merlin involving introduction of isoforms and mutated forms of the protein into Nf2-deficient cells. Specifically, mutations effecting merlin phosphorylation will be examined. The proposed project should shed light on the growth suppressive effects of merlin and possible cross-talk with the Rac/cdc42 pathway. This should lead to a better understanding of merlin function in normal cells and the consequences of its loss in tumor development. Such information will directly assist in the search for effective therapies. [unreadable] [unreadable]